Abstract:
:The prodrug activation system formed by the E. coli codA gene encoding cytosine deaminase (CD) and 5-fluorocytosine (5-FC) developed for selective cancer chemotherapy suffers from a sensitivity limitation in many tumour cells. In an attempt to improve the CD/5-FC suicide association, we combined the E. coli upp gene encoding uracil phosphoribosyltransferase (UPRT) with codA gene to create the situation prevailing in E. coli, a bacterium very efficient in metabolising 5-FC. The constitutive expression of the two genes cloned on an E. coli-animal cell shuttle plasmid either in a linked or in a fused configuration was evaluated in E. coli strains selected and engineered to mimic the 5-FC metabolism encountered in mammalian cells. The simultaneous expression of codA and upp genes generated a cooperative effect resulting in a dramatic increase in 5-FC sensitivity of cells compared to the expression of codA alone. Furthermore, it was shown that the association of UPRT with CD facilitated the uptake of 5-FC, in the situation where the drug penetrates cells by passive diffusion as in mammalian cells, by directly channeling 5-fluorouracil, the product of CD, to 5-fluoroUMP, the product of UPRT.
journal_name
FEMS Microbiol Lettjournal_title
FEMS microbiology lettersauthors
Tiraby M,Cazaux C,Baron M,Drocourt D,Reynes JP,Tiraby Gdoi
10.1111/j.1574-6968.1998.tb13205.xsubject
Has Abstractpub_date
1998-10-01 00:00:00pages
41-9issue
1eissn
0378-1097issn
1574-6968pii
S0378-1097(98)00365-6journal_volume
167pub_type
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